Azetidinone derivatives and process for the preparation of the same

ABSTRACT

This invention provides azetidinone derivatives represented by the formula ##STR1## and processes for preparing the same. The azetidinone derivatives are used as the intermediates for producing cephalosporin compounds useful as antibiotic agents.

This is a division of application Ser. No. 865,651 filed May 16, 1986,now U.S. Pat. No. 4,689,411; which is a continuation of Ser. No. 524,689filed Aug. 19, 1983, now abandoned; which is a continuation-in-part ofSer. No. 364,405 filed Apr. 1, 1982; now abandoned.

This invention relates to novel azetidinone derivatives and a processfor preparing the same and more particularly to azetidinone derivativesrepresented by the formula ##STR2## wherein R¹ is lower alkylsubstituted with aryl or with aryloxy, R² is lower alkyl substitutedwith aryl or with aryloxy or lower alkyl optionally substituted withhalogen, R³ is ##STR3## (wherein R⁴ is lower alkyl), ##STR4## (whereinR⁴ is as defined above),

    --S--SO.sub.2 --R.sup.5

(wherein R⁵ is aryl, ##STR5## (wherein R⁶ and R⁷ are the same ordifferent and lower alkyl or phenyl) or ##STR6## and X is hydrogen orhalogen. The aryl and aryloxy groups stated above may have substituents.

The present invention provides novel intermediates for the preparationof cephalosporine compounds represented by the formula (IV) (to behereinafter shown) which are useful as antibiotics.

The invention provides also processes for preparing the novelintermediates.

The invention further provides a novel process for preparingcephalosporine compounds represented by the formula (IV) from theforegoing intermediates.

Other features of the invention will be made apparent by the followingdescription.

Examples of the aryl-substituted lower alkyl groups represented by R¹ inthe formula (I) are benzyl, 2-phenylethyl, 3-phenylpropyl,4-phenylbutyl, p-hydroxybenzyl, p-nitrobenzyl, p-chlorobenzyl,p-methoxybenzyl, 2-(p-chlorophenyl)ethyl, 3-(p-methoxybenzyl)propyl,etc. Examples of the aryloxy-substituted lower alkyl groups representedby R¹ are phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl,4-phenoxybutyl, p-hydroxyphenoxymethyl, p-nitrophenoxymethyl,p-methoxyphenoxymethyl, 2-(p-methoxyphenoxy)ethyl,3-(p-nitrophenoxy)propyl and the like.

Examples of the lower alkyl groups represented by R² and substitutedwith aryl are benzyl, p-methoxybenzyl, p-chlorobenzyl, p-nitrobenzyl,diphenylmethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,2-(p-nitrophenyl)ethyl, 3-phenylpropyl, 3-(p-nitrophenyl)propyl, etc.Examples of the lower alkyl groups represented by R² and substitutedwith aryloxy are phenoxymethyl, p-nitrophenoxymethyl, 2-phenoxyethyl,3-phenoxypropyl, 4-phenoxybutyl, 2-(p-nitrophenoxy)ethyl,3-phenoxypropyl, 3-(p-nitrophenoxy)propyl, etc. Examples of the loweralkyl groups represented by R² and optionally substituted with halogenare methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,2-chloroethyl, 2,2,2-trichloroethyl, etc.

Examples of the lower alkyl groups represented by R⁴, R⁶ and R⁷ aremethyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl,n-hexyl, etc.

Exemplary of the aryl groups represented by R⁵ are phenyl,p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, p-hydroxyphenyl, etc.

Halogen atoms represented by X include chlorine, bromine, iodine, etc.

Among the azetidinone derivatives of the formula (I), preferred arethose having the formula ##STR7## wherein R¹, R², R³ and X are asdefined above, but when X is hydrogen, R³ is ##STR8## wherein R⁴ is asdefined above or ##STR9## wherein R⁶ and R⁷ are as defined above.

The azetidinone derivatives of the formula (I) are divided into twoclasses of compounds represented by the formulae (Ia) and (Ib)respectively. ##STR10## wherein R¹, R² and R³ are as defined above.##STR11## wherein R¹, R² and R³ are as defined above and X' is halogen.

Preferred examples of the compounds having the formula (Ia) are thecompounds represented by the formulae (Ic) and (Id) respectively.##STR12## wherein R¹, R² and R⁴ are as defined above. ##STR13## whereinR¹, R², R⁶ and R⁷ are as defined above.

Specific examples of the compounds having the formula (Ic) are shown inTable I given below wherein R¹, R² and R⁴ are specified.

                  TABLE I                                                         ______________________________________                                        R.sup.1        R.sup.2        R.sup.4                                         ______________________________________                                         ##STR14##     CH.sub.3       CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                                              ##STR15##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR16##                                                                                    ##STR17##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                              "              Cl.sub.3 CCH.sub.2                                                                           CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR18##     (CH.sub.3).sub.3 C                                                                           CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                              "                                                                                             ##STR19##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR20##                                                                                    ##STR21##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                              "                                                                                             ##STR22##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR23##                                                                                    ##STR24##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                              "              ClCH.sub.2 CH.sub.2                                                                          CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR25##                                                                                    ##STR26##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR27##                                                                                    ##STR28##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR29##                                                                                    ##STR30##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR31##     CH.sub.3       CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2 ).sub.3                      "              "              (CH.sub.3).sub.3 C                               ##STR32##                                                                                    ##STR33##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                              "                                                                                             ##STR34##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR35##                                                                                    ##STR36##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR37##     Cl.sub.3 CCH.sub.2                                                                           CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR38##     (CH.sub.3).sub.3 C                                                                           CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                              "                                                                                             ##STR39##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR40##                                                                                    ##STR41##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                              "                                                                                             ##STR42##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR43##                                                                                    ##STR44##     CH.sub.3                                        "              "              C.sub.2 H.sub.5                                 "              "              CH.sub.3 (CH.sub.2).sub.2                       "              "              (CH.sub.3).sub.2 CH                             "              "              CH.sub.3 (CH.sub.2).sub.3                       "              "              (CH.sub.3).sub.3 C                               ##STR45##     CH.sub.3       CH.sub.3                                        "                                                                                             ##STR46##     CH.sub.3 (CH.sub.2).sub.2                        ##STR47##                                                                                    ##STR48##     (CH.sub.3).sub.3 C                               ##STR49##     ClCH.sub.2 CH.sub.2                                                                          C.sub.2 H.sub.5                                  ##STR50##                                                                                    ##STR51##     CH.sub.3                                         ##STR52##                                                                                    ##STR53##     (CH.sub.3).sub.3 CH                              ##STR54##     ClCH.sub.2 CH.sub.2                                                                          CH.sub.3 (CH.sub.2).sub.2                        ##STR55##                                                                                    ##STR56##     CH.sub.3                                         ##STR57##                                                                                    ##STR58##     C.sub.2 H.sub.5                                  ##STR59##                CH.sub.3                                             ##STR60##                C.sub.2 H.sub.5                                     ______________________________________                                    

Specific examples of the compounds having the formula (Id) are shown inTable II given below wherein R¹, R², R⁶ and R⁷ are specified. ##STR61##

Specific examples of the compounds having the formula (Ib) are shown inTable III given below wherein R¹, R², R³ and X' are specified. ##STR62##

The compounds of the formulae (Ib), (Ic) and (Id) are all novelcompounds heretofore undisclosed in literature.

The azetidione derivatives of the formula (I) can be prepared by variousprocesses. Examples of the processes are hereinafter stated.

The compounds of the formula (Ia) wherein R³ is ##STR63## namely thecompounds of the formula (Ic), can be produced for example by subjectingto electrolysis an azetidione derivative of the formula ##STR64##wherein R¹ and R² are as defined above in a lower alcohol.

The compounds of the formula (II) useful as the starting material areknown and can be prepared by the process for example described inTetrahedron Letters 3001 (1973).

The compound of the formula (II) is electrolyzed in the presence oflower alcohol by passing the required amount of current through thesolution. Examples of useful lower alcohols are methanol, ethanol,propanol, isopropanol, butanol, tert-butyl alcohol, etc. According tothe present invention, these lower alcohols, which are usually used assolvents, are usable in admixture with any other suitable solvent.Useful solvents to be admixed with the lower alcohol includetetrahydrofuran, diethyl ether, dioxane and like ethers, acetonitrile,propionitrile and like nitriles, methylene chloride, chloroform, carbontetrachloride, dichloroethane and like hydrocarbon halides or mixturesthereof.

It is preferred to incorporate a supporting electrolyte in the reactionsystem. Useful supporting electrolytes include sulfuric acid, perchloricacid, phosphoric acid and like mineral acids, p-toluenesulfonic acid,methanesulfonic acid and like sulfonic acids, formic acid, acetic acid,propionic acid and like organic acids, etc.

The electrysis of the compound (II) can be performed at eithercontrolled potential or constant current. The cathode current density isusually in the range of about 1 to about 500 mA/cm², preferably about 5to about 200 mA/cm². The required amount of electric charge is usuallyabout 2 to about 50 F, preferably about 3 to about 40 F, per mole of thestarting material, although variable depending on the concentration ofthe substrate, the kind of the solvent, the type or shape of theelectrolytic bath, etc. Useful electrodes include those usually used,such as those of platinum, carbon, stainless steel, titanium, nickel orthe like. The reaction temperature is not particularly limited as far asit is below a level at which there occurs the decomposition orconversion of the starting material and reaction product. It rangesusually from about -70° to about 80° C., preferably from about -30° toabout 60° C., most preferably about -20° to about 30° C. Theelectrolytic bath is used with or without a diaphragm.

The compounds of the formula (Ia) wherein R³ is ##STR65## namely thecompounds of the formula (Id), are prepared by reacting the azetidinonederivative of the formula (II) with the ester of phosphorous acidrepresented by the formula ##STR66## wherein R⁸ is lower alkyl or phenyland R⁶ and R⁷ are as defined above. The esters of phosphorous acidhaving the formula (III) are known and readily available. Examples ofthe compounds (III) are trimethylphosphite, triethylphosphite,triphenylphosphite, methyldiethylphosphite, dimethylethylphosphite,methyldiphenylphosphite, dimethylphenylphosphite,diethylphenylphosphite, tri-(n-propyl)phosphite, tri-(n-butyl)phosphite,di-(n-propyl)phenylphosphite, di-(n-butyl)phenylphosphite, etc.

According to the present invention, the reaction between the compoundsof the formulae (II) and (III0 is carried out without a solvent or witha suitable inert solvent. Useful inert solvents are, for example,methylene chloride, chloroform, carbon tetrachloride, dichloroethane andlike hydrocarbon halides, diethyl ether, dibutyl ether, dioxane,tetrahydrofuran and like ethers, acetonitrile, butyronitrile and likenitriles, benzene, toluene, chlorobenzene and like aromatichydrocarbons, hexane, cyclohexane, heptane, pentane and likehydrocarbons and mixtures thereof, etc. The amount of the compoundhaving the formula (III) relative to that of the compound (II), is notparticularly limited but widely variable. The compound of the formula(III) is used in an amount of usually about 0.1 to about 10 moles,preferably about 1.5 to about 3 moles, per mole of the compound (II).The reaction is effected at any of ambient, increased and reducedtemperatures, usually at about -30° about 100° C., preferably about -20°to 80° C.

The compounds of the formula (Ia) wherein R³ is ##STR67## cam beprepared by the process disclosed in Japanese Unexamined PatentPublication No. 102669/1974. Similarly those wherein R³ is

    --S--SO.sub.2 --R.sup.5

can be produced by the process taught by Tetrahedron Letters 3001 (1973)and those wherein R³ is ##STR68## by the process described inTetrahedron Letters 4897 (1970).

The compounds of the formula (Ib) are produced by subjecting thecompound of the formula (Ia) to electrolysis in the presence ofhydrohalogenic acid and/or halide.

Useful hydrohalogenic acids include a wide variety of known compoundssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, amongwhich the hydrochloric acid is preferred. Usable as the halide arevarious compounds such as ammonium chloride, tetramethylammoniumchloride, benzyltrimethylammonium chloride and like quaternary ammoniumchlorides, lithium chloride, sodium chloride, potassium chloride andlike alkali metal chlorides, magnesium chloride, barium chloride,calcium chloride and like alkaline earth metal chlorides and otherchlorides, ammonium bromide, tetramethylammonium bromide,tetraethylammonium bromide, benzyltrimethylammonium bromide and likequaternary ammonium bromides, sodium bromide, cerium bromide, lithiumbromide and like alkali metal bromides, magnesium bromide and likealkaline earth metal bromides and other bromides, ammonium iodide,tetramethylammonium iodide, tetraethylammonium iodide and likequaternary ammonium iodides, lithium iodide, potassium iodide, sodiumiodide and like alkali metal iodides and like other iodides, etc. Theamounts of the hydrohalogenic acid and/or halide to be used are notparticularly limited but widely variable. They are usually used in anamount of about 0.5 to about 10 moles, preferably about 1 to about 8moles, per mole of the compound having the formula (Ia). The halide iseffective when used in conjunction with mineral acid or organic acid.Examples of useful mineral acids are sulfuric acid, sodiumhydrogensulfate, potassium hydrogensulfate, phosphorica acid, boricacid, etc. Useful organic acids include formic acid, acetic acid,propionic acid, butyric acid, oxalic acid, citric acid and likecarboxylic acid, p-toluenesulfonic acid, methanesulfonic acid and likesulfonic acids, etc. It is preferred to use the mineral acid or organicacid in an amount of about 0.5 to about 10 mole, preferably about 1 toabout 8 mole, per mole of the compound (Ia). Generally used as thereaction medium is water, organic solvent or a mixture thereof. Usableas the organic solvent are various solvents inert to halogenation suchas methyl formate, ethyl formate, methyl acetate, ethyl acetate, butylacetate, ethyl propionate and like esters, dichloromethane, chloroform,carbon tetrachloride, dichloroethane, dibromoethane, chlorobenzene andlike hydrocarbon halides, diethyl ether, dibutyl ether, dioxane,tetrahydrofuran and like ethers, acetonitriles, butyronitriles and likenitriles, pentane, hexane, cyclohexane and like hydrocarbons, carbondisulfide, etc.

The electrolysis of the compound (Ia) can be performed at eithercontrolled potential or constant current. The cathode current density isusually in the range of about 1 to about 500 mA/cm², preferably about 5to about 200 mA/cm². The required amount of electric charge is usuallyabout 2 to about 50 F, preferably about 3 to about 40 F, per mole of thestarting material, although variable depending on the concentration ofthe substrate, the kind of the solvent, the type or shape of theelectrolytic bath, etc. Useful electrodes include those usually used,such as those of platinum, carbon, stainless steel, titanium, nickel orthe like. The reaction temperature is not particularly limited as far asit is below a level at which there occurs the decomposition orconversion of the starting material and reaction product. It is usuallyabout -30° to about 60° C., preferably about -20° to about 30° C. Theelectrolytic bath is used with or without a diaphragm.

The compounds of this invention are each readily separated from thereaction mixture and purified by the usual means such as solventextraction, column chromatography, etc.

According to the processes stated above, the end product as contemplatedcan be prepared in a high yield by a simplified procedure under moderateconditions. Further the processes of this invention facilitate theseparation and purification of the compounds and are free from theproblem arising from the disposal of by-products. Therefore, the presentprocesses are extremely advantageous from commercial points of view.

The compounds of the formula (I) are useful as the intermediates for thesynthesis of penicillin- and cephalosporin-type antibiotics. Forexample, cephalosporin compounds (IV) useful as antibiotic agents can bederived from the compounds of the formula (Ib) according to thefollowing reaction formula in which R¹, R², R³ and X' are as definedabove. ##STR69##

The compound of the formula (Ia) is advantageously used as theintermediate for the synthesis of compound of the formula (Ib) fromwhich the compound of the formula (IV) is derived as the end product.

In the course of the reaction, a base is permitted to act on thecompound of the formula (Ib) in the presence of an organic solvent,whereby the compound of the formula (IV) is prepared.

Exemplary of useful organic solvents are methanol, ethanol, isopropanoland like alcohols, acetonitrile, butyronitrile and like nitriles,acetone, methyl ethyl ketone and like ketones, formamidedimethylformamide, diethylformamide, dimethylacetamide and like amides,etc. These solvents are used singly or in mixture. It is preferred touse polar solvents singly or in admixture, such as formamide,diethylformamide, dimethylacetamide, etc. Useful bases are for examplepotassium hydroxide, sodium hydroxide and like metal hydroxides,potassium acetate, sodium acetate and like alkali metal salts ofcarboxylic acids, triethylamine, 1,8-diazabicyclo[5,4,0]7-undecene,1,5-diazabicyclo[4,3,0]5-nonenepyridine and like amines, potassiumiodide, sodium iodide and like alkali metal halides, ammonia, ammoniawater and the like among which ammonia and ammonia water are preferred.The amount of the base to be used is not particularly limited but isdetermined over a wide range. The base is used in an amount of usuallyabout 0.1 to about 10 moles, preferably about 1 to about 1.5 moles, permole of the compound (Ib). The reaction temperature is in the range ofusually about -78° to about 40° C., preferably about -50° to about 5° C.The reaction time is variable depending on the reaction temperature andthe type of starting material, but the reaction usually takes about 5minutes to about 10 hours to go to completion.

The compound of the formula (IV) thus preprared is easily separated fromthe reaction mixture and purified by the usual means such as solventextraction, column chromatography, etc.

The foregoing processes of the present invention are able to produce thecompounds of the formula (IV) in high yields with high purity by asimplified procedure.

For a better understanding of the invention examples are given below.

EXAMPLE 1

A 250.3 mg quantity of a compound (II) wherein R¹ is benzyl and R² ismethyl was dissolved in 50 ml of methanol. To the solution was added 0.4ml of concentrated sulfuric acid. Electrolysis was continued for 2 hourswith stirring at a temperature of 0° to 2° C. and a cathode currentdensity of 5 mA/cm² by using platinum electrodes (4×3 cm²). After thecompletion of the reaction, the reaction mixture was extracted withethyl acetate, washed with a saturated aqueous solution of sodiumhydrogencarbonate and then with a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. The solvent wasremoved from the dried product at reduced pressure. The residue wasseparated and purified by silica gel column chromatography by using a3:1 benzene-ethyl acetate mixture as a developer, giving 167.9 mg of acompound (Ic) wherein R¹ is benzyl and R² and R⁴ are both methyl. Yield88%.

NMR (CDCl₃, δ, ppm): 1.99 (s, 3H), 3.42 (s, 3H), 3.56 (s, 2H), 3.72 (s,3H), 4.52 (q, 1H), 4.70, 4.84, 5.05, 5.16 (4s, 4H), 6.71 (d, 1H), 7.27(s, 5H).

EXAMPLE 2

A 50.2 mg quantity of a compound (II) wherein R¹ is benzyl and R² ismethyl was dissolved in 4 ml of methanol and 4.5 ml of tetrahydrofuran.To the solution was added 0.07 ml of concentrated sulfuric acid. Byusing platinum electrodes, electrolysis was continued for 1 hour and 35minutes at a temperature of -14° to -12° C. and a cathode currentdensity of 5 mA/cm². After the reaction was completed, the subsequentprocedure of Example 1 was repeated, giving 30.2 mg of a compound (Ic)wherein R¹ is benzyl and R² and R⁴ are both methyl. Yield 79%.

The compound thus obtained was identified by IR and NMR.

EXAMPLE 3

A 50.6 mg quantity of a compound (II) wherein R¹ is benzyl and R² ismethyl was dissolved in 8 ml of methanol. To the solution were added0.07 ml of concentrated sulfuric acid. By using carbon electrodes,electrolysis was continued for 45 minutes at a temperature of 0° to 2°C. and a cathode current density of 10 mA/cm². After the completion ofthe reaction, the subsequent procedure described in Example 1 produced30.2 mg of a compound (Ic) wherein R¹ is benzyl and R² and R⁴ are bothmethyl. Yield 77%.

The compound thus prepared was identified with IR and NMR.

EXAMPLE 4

A 49.5 mg quantity of a compound (II) wherein R¹ is benzyl and R² ismethyl was dissolved in 8 ml of methanol. To the solution were added0.07 ml of concentrated sulfuric acid and 42 mg of copper sulfate. Byusing platinum electrodes, electrolysis was continued for 1 hour and 15minutes at a temperature of 0° to 2° C. and a cathode current density of10 mA/cm². During the electrolysis, the direction of current was alteredevery 30 seconds. After the completion of the reaction, the subsequentprocedure of Example 1 produced 32.07 mg of a compound (Ic) wherein R¹is benzyl and R² and R⁴ are both methyl. Yield 84%.

The compound thus obtained was identified by IR and NMR.

EXAMPLES 5 TO 24

Using the compounds (II) as the starting material wherein R¹ and R² areas defined in Table 1 below, the same procedure as in Examples 1 wasrepeated, affording compounds exhibiting properties (IR and NMR) shownin Table 1 and having the formula ##STR70## wherein R¹ and R² are asdefined below in Table 1 and Ph is phenyl (the same in subsequent tablesgiven hereinafter).

                                      TABLE 1                                     __________________________________________________________________________    Example                                                                            R.sup.1                                                                             R.sup.2      IR (cm.sup.-1)                                                                      NMR (δ, ppm)                              __________________________________________________________________________    5    PhCH.sub.2                                                                          CH.sub.3     1775  1.89 (s, 3H), 3.42 (s, 3H), 3.56 (s, 2H),                               1735  3.72 (s, 3H), 4.52 (d, J=6.2Hz, 1H),                                    1670  4.70 (s, 1H), 4.84 (s, 1H), 5.05 (s, 1H),                                     5.15 (s, 1H), 6.70 (d, J=6.2Hz, 1H),                                          7.27 (s, 5H)                                    6    PhCH.sub.2                                                                           ##STR71##   1780 1741 1669                                                                      1.86 (s, 3H), 3.42 (s, 3H), 3.56 (s, 2H),                                     4.52 (d, J=6.2Hz, 1H), 4.65 (s, 1H), 4.79                                     (s, 1H), 5.02 (s, 1H), 5.16 (s, 1H), 5.18                                     (s, 2H), 6.5 (d, J=6.2Hz, 1H), 7.26 (s,                                       5H), 7.50 (d, 9.5Hz, 2H), 8.20 (d, 9.5Hz,                                     2H)                                             7    PhCH.sub.2                                                                           ##STR72##   1780 1745 1675                                                                      1.79 (s, 3H), 3.43 (s, 3H), 3.52 (s, 3H),                                     4.49 (d, J= 6.2Hz, 1H), 4.63 (s, 1H), 4.77                                    (s, 1H), 4.98 (s, 1H), 5.10 (s, 1H), 6.3                                      (d, J=6.2Hz, 1H), 6.92 (s, 1H), 7.0-8.0 (m,                                   15H)                                            8    PhCH.sub.2                                                                          CH.sub.2 CCl.sub.3                                                                         1778  1.89 (s, 3H), 3.40 (s, 3H), 3.66 (s, 2H),                               1735  4.52 (d, J=6.2Hz, 1H), 4.75 (bs, 3H),                                   1680  4.89 (s, 1H), 5.10 (s, 1H), 5.16 (s, 1H),                                     6.6 (d, J=6.2Hz, 1H), 7.29 (s, 5H)              9    PhCH.sub.2                                                                          tert-C.sub.4 H.sub.9                                                                       1768  1.45 (s, 9H), 1.85 (s, 3H), 3.42 (s, 3H),                               1730  3.55 (s, 2H), 4.50 (d, J=6.2Hz, 1H),                                    1675  4.68 (s, 1H), 4.83 (s, 1H), 5.03 (s, 1H),                                     5.16 (s, 1H), 6.5 (d, J=6.2Hz, 1H),                                           7.28 (s, 5H),                                   10   PhOCH.sub.2                                                                         CH.sub.3     1776  1.95 (s, 3H), 3.43 (s, 3H), 3.76 (s, 3H),                               1740  4.53 (s, 2H), 4.62 (d, J=6.2Hz, 1H),                                    1680  4.70 (s, 1H), 4.84 (s, 1H), 5.06 (s, 1H),                                     5.27 (s, 1H), 6.5-7.5 (m, 6H)                   11   PhOCH.sub.2                                                                          ##STR73##   1780 1745 1690                                                                      1.97 (s, 3H), 3.44 (s, 3H), 4.52 (s, 2H),                                     4.61 (d, J=6.2Hz, 1H), 4.66 (s, 1H), 4.79                                     (s, 1H), 5.02 (s, 1H), 5.19 (s, 2H), 5.24                                     (s, 1H), 6.5-8.4 (m, 10H)                       12   PhOCH.sub.2                                                                          ##STR74##   1780 1743 1688                                                                      1.90 (s, 3H), 3.43 (s, 3H), 4.49 (s, 2H),                                     4.57 (d, J=6.2Hz, 1H), 4.63 (s, 1H), 4.77                                     (s, 1H), 4.99 (s, 1H), 5.22 (s, 1H),                                          6.5-8.0 (m, 17H)                                13   PhOCH.sub.2                                                                         CH.sub.2 CCl.sub.3                                                                         1780  1.95 (s, 3H), 3.41 (s, 3H), 4.53 (s, 2H),                               1742  4.63 (m, 2H), 4.77 (m, 3H), 5.01 (s, 1H),                               1680  5.26 (s, 1H), 6.5-7.5 (m, 6H)                   14   PhOCH.sub.2                                                                         tert-C.sub.4 H.sub.9                                                                       1778  1.47 (s, 9H), 1.94 (s, 3H), 3.44 (s, 3H),                               1740  4.54 (s, 2H), 4.62 (d, J=6.2Hz, 1H),                                    1667  4.71 (s, 1H), 4.84 (s, 1H), 5.05 (s, 1H),                                     5.26 (s, 1H), 6.5-7.5 (m, 6H)                   15   PhCH.sub.2                                                                          CH.sub.3     1780  3.40 (s, 3H), 3.52 (s, 2H), 3.71 (s, 3H),                               1760  4.20 (bs, 2H), 4.46 (d, J=7Hz, 1H),                                     1675  4.82 (s, 1H), 4.95 (s, 1H), 5.33 (s, 1H),                                     5.52 (s, 1H), 6.42 (d, J=7Hz, 1H),                                            7.23 (s, 5H)                                    16   PhCH.sub.2                                                                           ##STR75##   1780 1755 1675                                                                      3.41 (s, 3H), 3.52 (s, 2H), 4.20 (bs, 2H),                                    4.46 (d, J=7Hz, 1H), 4.77 (s, 1H), 4.90 (s,                                   1H), 5.18 (s, 2H), 5.29 (s, 1H), 5.52 (s,                                     1H), 6.50 (d, J=7Hz, 1H), 7.25 (s, 5H),                                       7.48 (d, 9.5Hz, 2H), 8.17 (d, 9.5Hz, 2H)        17   PhCH.sub.2                                                                           ##STR76##   1775 1755 1673                                                                      3.42 (s, 3H), 3.47 (s, 2H), 4.24 (bs, 2H),                                    4.41 (d, J=7Hz, 1H), 4.73 (s, 1H), 4.88 (s,                                   1H), 5.26 (s, 1H), 5.47 (s, 1H), 6.44 (d,                                     J=7Hz, 1H), 6.92 (s, 1H), 7.0-8.0 (m, 15H)      18   PhCH.sub.2                                                                          CH.sub.2 CCl.sub.3                                                                         1785  3.38 (s, 3H), 3.62 (s, 2H), 4.30 (bs, 2H),                              1760  4.51 (d, J=7Hz, 1H), 4.80 (bs, 2H),                                     1678  4.87 (s, 1H), 5.00 (s, 1H), 5.38 (s, 1H),                                     5.52 (s, 1H), 6.3 (d, J=7Hz, 1H),                                             7.3 (s, 5H)                                     19   PhCH.sub.2                                                                          tert-C.sub.4 H.sub.9                                                                       1772  1.47 (s, 9H), 3.40 (s, 3H), 3.51 (s, 2H),                               1763  4.18 (bs, 2H), 4.44 (d, J=7Hz, 1H),                                     1665  4.79 (s, 1H), 4.94 (s, 1H), 5.31 (s, 1H),                                     5.52 (s, 1H), 6.6 (d, J=7Hz, 1H),                                             7.24 (s, 5H)                                    20   PhOCH.sub.2                                                                         CH.sub.3     1785  3.42 (s, 3H), 3.55 (s, 3H), 4.22 (bs, 2H),                              1760  4.56 (d, 7Hz, 1H), 4.52 (s, 2H),                                        1683  4.85 (s, 1H), 4.97 (s, 1H), 5.35 (s, 1H),                                     5.54 (s, 1H), 6.5-7.5 (m, 6H)                   21   PhOCH.sub.2                                                                          ##STR77##   1773 1756 1668                                                                      3.43 (s, 3H), 4.24 (bs, 2H), 4.55 (d, 7Hz,                                    1H), 4.53 (s, 2H), 4.80 (s, 1H), 5.02 (s,                                     1H), 5.20 (s, 2H), 5.30 (s, 1H), 5.54 (s,                                     1H), 6.45 (d, J=7Hz, 1H), 6.8-8.3 (m, 9H)       22   PhOCH.sub.2                                                                          ##STR78##   1783 1754 1678                                                                      3.43 (s, 3H), 4.26 (bs, 2H), 4.51 (d,                                         J=7Hz, 1H), 4.47 (s, 2H), 4.80 (s, 1H),                                       4.91 (s, 1H), 5.29 (s, 1H), 5.49 (s, 1H),                                     6.3 (d, J=7Hz, 1H), 6.91 (s, 1H), 7.0-8.0                                     (m, 15H)                                        23   PhOCH.sub.2                                                                         CH.sub.2 CCl.sub.3                                                                         1780  3.41 (s, 3H), 4.23 (bs, 2H),                                            1765  4.58 (d, 7Hz, 1H), 4.57 (s, 2H),                                        1690  4.75 (bs, 2H), 4.90 (s, 1H), 5.02 (s, 1H),                                    5.40 (s, 1H), 5.53 (s, 1H),                                                   6.6-7.5 (m, 6H)                                 24   PhOCH.sub.2                                                                         tert-C.sub.4 H.sub.9                                                                       1785  1.45 (s, 9H), 3.40 (s, 3H), 4.21 (bs, 2H),                              1758  4.53 (m, 3H), 4.82 (s, 1H), 4.96 (s, 1H),                               1680  5.33 (s, 1H), 5.50 (s, 1H), 6.6-7.5 (m,         __________________________________________________________________________                                  6H)                                         

EXAMPLE 25

A 100 mg quantity of a compound (II) wherein R¹ is phenoxymethyl and R²is methyl was dissolved in 1 ml of benzene. To the solution was added0.45 ml of trimethyl phosphite, i.e. a compound (III) wherein R⁶, R⁷ andR⁸ are all methyl. The mixture was refluxed with heating for 1 hour. Thereaction mixture was cooled to room temperature and extracted with 10 mlof ethyl acetate. The extract was washed with a 5% aqueous solution ofsodium hydroxide and then with a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. The solvent wasremoved from the dried product at reduced pressure. The residue wasseparated and purified by silica gel column chromatography using a 1:1benzene-ethyl acetate mixture as a developer. As a result, there wasobtained 84.0 mg of a compound (Id) wherein R¹ is phenoxymethyl and R²,R⁶ and R⁷ are all methyl. Yield 94%.

IR (CHCl₃, cm⁻¹) 1782, 1740, 1685.

NMR (CDCl₃, δ, ppm): 1.90 (s, 3H), 3.59 (s, 3H), 3.75 (s, 3H), 3.76 (s,3H), 4.52 (s, 2H), 4.81 (s, 1H), 5.02 (s, 1H), 5.11 (s, 1H), 5.48-5.80(m, 2H), 6.8-7.4 (5H), 7.67 (d, 1H).

EXAMPLES 26 TO 37

The procedure of Example 25 was repeated by using, as the startingmaterial, compounds (II) wherein R¹ and R² are as defined in Table 2given below and compounds (III) wherein R⁶, R⁷ and R⁸ are as defined inTable 2, and employing the conditions as indicated in Table 3 givenbelow. Thus compounds (Id) having the formula ##STR79## were prepared inthe yields and with properties shown in Tables 3 to 5.

                                      TABLE 2                                     __________________________________________________________________________    Compound (II)           Compound (III)                                        Example                                                                            R.sup.1                                                                             R.sup.2                                                                             Amount (mg)                                                                          R.sup.6                                                                           R.sup.7                                                                           R.sup.8                                                                           Amount (ml)                               __________________________________________________________________________    26   PhOCH.sub.2 --                                                                      CH.sub.3 --                                                                         100    C.sub.2 H.sub.5 --                                                                C.sub.2 H.sub.5 --                                                                H   0.27                                      27   PhOCH.sub.2 --                                                                      PhCH.sub.2 --                                                                       50     C.sub.2 H.sub.5 --                                                                C.sub.2 H.sub.5 --                                                                H   0.5                                       28   PhOCH.sub.2 --                                                                      CCl.sub.3 CH.sub.2 --                                                               50     C.sub.2 H.sub.5 --                                                                C.sub.2 H.sub.5 --                                                                H   0.5                                       29   PhOCH.sub.2 --                                                                      PhCH.sub.2 --                                                                       50     CH.sub.3 --                                                                       CH.sub.3 --                                                                       CH.sub.3 --                                                                       0.5                                       30   PhOCH.sub.2 --                                                                      PhCH.sub.2 --                                                                       50     Ph--                                                                              Ph--                                                                              H   0.5                                       31   PhOCH.sub.2 --                                                                      PhCH.sub.2 --                                                                       50     Ph--                                                                              Ph--                                                                              H   0.2                                       32   PhCH.sub.2 --                                                                       CH.sub.3 --                                                                         55     CH.sub.3 --                                                                       CH.sub.3 --                                                                       H   0.5                                       33   PhCH.sub.2 --                                                                       CH.sub.3 --                                                                         50     Ph--                                                                              Ph--                                                                              Ph--                                                                              1.0                                       34   PhCH.sub.2 --                                                                       CH.sub.3 --                                                                         500    C.sub.2 H.sub.5 --                                                                C.sub.2 H.sub.5 --                                                                H   5                                         35   PhCH.sub.2 --                                                                       PhCH.sub.2 --                                                                       50     C.sub.2 H.sub.5 --                                                                C.sub.2 H.sub.2 --                                                                H   0.5                                       36   PhCH.sub.2 --                                                                       PhCH.sub.2 --                                                                       50     CH.sub.3 --                                                                       CH.sub.3 --                                                                       CH.sub.3 --                                                                       0.5                                       37   PhCH.sub.2 --                                                                       PhCH.sub.2 --                                                                       50     Ph--                                                                              Ph--                                                                              H   0.5                                       __________________________________________________________________________

                  TABLE 3                                                         ______________________________________                                                               Temperature                                                                              Time Yield                                  Example                                                                              Solvent         (°C.)                                                                             (hr) (%)                                    ______________________________________                                        26     Benzene-acetonitrile                                                                          18-20      18   83                                            (1 ml) (0.5 ml)                                                        27     None            60-62      4    93                                     28     "               58-61      3.5  97.5                                   29     "               50-55      10   85                                     30     "               50-53      3.5  85                                     31     Tetrahydrofuran(0.5 ml)                                                                       45-55      10   88                                     32     None            55-60      11.5 96                                     33     "               58-60      20   76                                     34     "               58-61      3.8  95                                     35     "               55-65      4    89                                     36     "               60-65      3    83                                     37     "               58-63      5    78                                     ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                               Compound (Id)                                                          Example  R.sup.1    R.sup.2    R.sup.6                                                                              R.sup.7                                 ______________________________________                                        26       PhOCH.sub.2 --                                                                           CH.sub.3 --                                                                              C.sub.2 H.sub.5 --                                                                   C.sub.2 H.sub.5 --                      27       PhOCH.sub.2 --                                                                           PhCH.sub.2 --                                                                            C.sub.2 H.sub.5 --                                                                   C.sub.2 H.sub.5 --                      28       PhOCH.sub.2 --                                                                           CCl.sub.3 CH.sub.2 --                                                                    C.sub.2 H.sub.5 --                                                                   C.sub.2 H.sub.5 --                      29       PhOCH.sub.2 --                                                                           PhCH.sub.2 --                                                                            CH.sub.3 --                                                                          CH.sub.3 --                             30, 31   PhOCH.sub.2 --                                                                           PhCH.sub.2 --                                                                            Ph--   Ph--                                    32       PhCH.sub.2 --                                                                            CH.sub.3 --                                                                              CH.sub.3 --                                                                          CH.sub.3 --                             33       PhCH.sub.2 --                                                                            CH.sub.3 --                                                                              Ph--   Ph--                                    34       PhCH.sub.2 --                                                                            CH.sub.3 --                                                                              C.sub.2 H.sub.5 --                                                                   C.sub.2 H.sub.5 --                      35       PhCH.sub.2 --                                                                            PhCH.sub.2 --                                                                            C.sub.2 H.sub.5 --                                                                   C.sub.2 H.sub.5 --                      36       PhCH.sub.2 --                                                                            PhCH.sub.2 --                                                                            CH.sub.3 --                                                                          CH.sub.3 --                             37       PhCH.sub.2 --                                                                            PhCH.sub.2 --                                                                            Ph--   Ph--                                    ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        IR                                                                            Example (.sup.ν max, cm.sup.-1)                                                                .sup.1 H - NMR ( δ, ppm)                            ______________________________________                                        26      1780        1.31 (t, 6H), 1.94 (s, 3H),                                       1740        3.82 (s, 3H), 3.9-4.4 (m, 4H),                                    1685        4.60 (s, 2H), 4.91 (s, 1H),                                                   5.10 (s, 1H), 5.23 (s, 1H),                                                   5.4-6.0 (m, 2H), 6.9-7.6 (m, 5H),                                             7.95 (d, 2H)                                              27      1783        1.25 (t, 6H), 1.87 (s, 3H),                                       1745        3.7-4.4 (m, 4H), 4.53 (s, 2H),                                    1690        4.81 (s, 1H), 5.02 (s, 1H),                                                   5.10 (s, 1H), 5.15 (s, 2H),                                                   5.4-5.8 (m, 2H), 6.7-7.5 (10H),                                               7.80 (d, 2H)                                              28      1785        1.31 (t, 6H), 1.93 (s, 3H),                                       1748        3.8-4.4 (m, 4H), 4.58 (s, 2H),                                    1688        4.75 (s, 2H), 4.91 (s, lH),                                                   5.10 (s, 1H), 5.24 (s, 1H),                                                   5.3-5.9 (m, 2H), 6.9-7.6 (m, 5H),                                             7.84 (d, 2H)                                              29      1783        1.90 (s, 3H), 3.59 (s, 3H),                                       1745        3.76 (s, 3H), 4.52 (s, 2H),                                       1687        4.81 (s, 1H), 5.02 (s, 1H),                                                   5.11 (s, 1H), 5.18 (s, 2H),                                                   5.48-5.8 (m, 2H), 6.8-7.4 (10H),                                              7.67 (d, 1H)                                              30, 31  1785        1.93 (s, 1H), 4.52 (s, 2H),                                       1747        4.81 (s, 1H), 5.02 (s, 1H),                                       1690        5.10 (s, 1H), 5.11 (s, 1H),                                                   5.20 (s, 2H), 5.4-5.9 (m, 2H),                                                6.8-7.5 (10H), 7.60 (d, 1H)                               32      1780        1.89 (s, 3H), 3.59 (s, 3H),                                       1745        3.63 (s, 2H), 3.70 (s, 3H),                                       1673        3.75 (s, 3H), 4.76 (s, 1H),                                                   5.01 (s, 1H), 5.11 (s, 1H)                                                    5.30-5.8 (m, 2H), 6.70 (d, 1H),                                               7.30 (s, 5H)                                              33      1782        1.86 (s, 3H), 3.37 (s, 3H),                                       1740        3.39 (s, 2H), 4.75 (s, 1H),                                       1660        4.95 (s, 1H), 5.05 (s, 1H),                                                   5.18 (s, 2H), 5.1-5.7 (m, 2H),                                                6.55 (d, 1H), 7.2 (bs, 15H)                               34      1780        1.29 (t, 6H), 1.87 (s, 3H),                                       1740        3.63 (s, 2H), 3.74 (s, 3H),                                       1673        3.8-4.3 (m, 4H), 4.76 (s, 1H),                                                5.0 (s, 1H), 5.11 (s, 1H),                                                    5.26-5.75 (m, 2H), 6.70 (d, 1H),                                              7.26 (s, 5H)                                              35      1780        1.24 (t, 6H), 1.86 (s, 3H),                                       1740        3.58 (s, 2H), 3.7-4.3 (m, 4H),                                    1670        4.84 (s, 1H), 4.98 (s, 1H),                                                   5.08 (s, 1H), 5.18 (s, 2H),                                                   5.3-5.8 (m, 2H), 7-7.5 (10H),                                                 7.72 (d, 1H)                                              36      1780        1.86 (s, 3H), 3.57 (s, 2H),                                       1740        3.60 (s, 3H), 3.76 (s, 3H),                                       1665        4.84 (s, 1H), 4.95 (s, 1H),                                                   5.07 (s, 1H), 5.18 (s, 2H),                                                   5.3-5.9 (m, 2H), 6.9-7.5 (11H)                            37      1787        1.86 (s, 3H), 3.39 (s, 2H),                                       1745        4.75 (s, 1H), 4.95 (s, 1H),                                       1660        5.05 (s, 1H), 5.15 (s, 2H),                                                   5.1-5.9 (m, 2H), 6.55 (d, 1H),                                                7.2 (bs, 20H)                                             ______________________________________                                    

EXAMPLE 38

The procedure of Example 25 was followed replacing the starting materialwith a compound (II) wherein R¹ is p-methoxybenzyl and R² isp-chlorobenzyl and a compound (III) wherein R⁶ is methyl, R⁷ is methylwhen R⁸ is phenyl or R⁷ is phenyl when R⁸ is methyl. As a result, therewere prepared two types of compounds (Id) at the same time, namely thecompound (Id) [Compound (A)] wherein R¹ is p-methoxybenzyl, R² isp-chlorobenzyl, R⁶ is methyl and R⁷ is phenyl in a yield of 54% and thecompound (Id) [Compound (B)] wherein R¹ is p-methoxybenzyl, R² isp-chlorobenzyl, R⁶ and R⁷ are both methyl in a yield of 32%. Compounds(A) and (B) were identified by IR and NMR.

    ______________________________________                                        Elementary analysis                                                                    C           H      N                                                 ______________________________________                                        Compound (A)                                                                  Calcd. (%):                                                                              56.49         4.89   4.25                                          Found (%): 56.52         4.88   4.22                                          Compound (B)                                                                  Calcd. (%):                                                                              52.30         5.07   4.69                                          Found (%): 52.28         5.05   4.73                                          ______________________________________                                    

EXAMPLE 39

The procedure of Example 25 was repeated by using a compound (II)wherein R¹ is phenoxymethyl and R² is p-nitrobenzyl and a compound (III)wherein R⁶, R⁷ and R⁸ are all methyl. As a result, there was prepared acompound (Id) wherein R¹ is phenoxymethyl, R² is p-nitrobenzyl and R⁶and R⁷ are both methyl. Yield 86%. The compound (Id) was identified byIR and NMR.

    ______________________________________                                        Elementary analysis                                                                    C           H      N                                                 ______________________________________                                        Calcd. (%):                                                                              50.59         4.75   7.08                                          Found (%): 50.62         4.76   7.11                                          ______________________________________                                    

EXAMPLE 40

The procedure of Example 25 was followed by using a compound (II)wherein R¹ is benzyl and R² is diphenylmethyl and a compound (III)wherein R⁶, R⁷ and R⁸ are all phenyl, giving a compound (Id) wherein R¹is benzyl and R² is diphenylmethyl and R⁶ and R⁷ are both phenyl. Yield84%. The compound (Id) was identified by IR and NMR.

    ______________________________________                                        Elementary analysis                                                                    C           H      N                                                 ______________________________________                                        Calcd. (%):                                                                              67.19         5.10   3.82                                          Found (%): 67.16         5.10   3.83                                          ______________________________________                                    

EXAMPLE 41

A compound (Id) wherein R¹ is benzyl, R² is tert-butyl and R⁶ and R⁷ areboth methyl was prepared by repeating the procedure of Example 25 usinga compound (II) wherein R¹ is benzyl and R² is tert-butyl and a compound(III) wherein R⁶ and R⁷ are both methyl and R⁸ is phenyl. Yield 89.5%.The compound was identified by IR and NMR.

    ______________________________________                                        Elementary analysis                                                                    C           H      N                                                 ______________________________________                                        Calcd. (%):                                                                              52.99         6.28   5.62                                          Found (%): 52.95         6.30   5.65                                          ______________________________________                                    

EXAMPLE 42

Into a reactor were placed 500 mg of a compound (Ia) wherein R¹ isbenzyl, R² is methyl, R³ is ##STR80## and R⁴ is methyl, 50 ml ofmethylene chloride, 10.0 g of sodium chloride, 30 ml of water and 0.8 mlof acetic acid. The mixture was stirred to obtain a solution comprisingtwo liquid phases. Electrolysis was continued at a temperature of 15° to17° C. and a cathode current density of 10 mA/cm² by using platinumelectrodes (1.5×2 cm²) and passing an electric charge of 3 F per mole ofthe starting material while stirring the mixture for 40 minutes. Afterthe completion of the electrolysis, the organic phase was separated andwashed with a saturated aqueous solution of sodium hydrogencarbonate andthen with that of sodium chloride. The resulting product was dried overanhydrous sodium sulfate. The organic solvent was removed at reducedpressure. The residue was purified by silica gel column chromatographywith use of a 5:1 benzene-ethyl acetate mixture as a developer,affording 445 mg of a compound (Ib) wherein R¹ is benzyl, R² is methyl,R³ is ##STR81## R⁴ is methyl and X is Cl. Yield 82%.

IR (.sup.ν max, cm⁻¹): 2970, 1780, 1760, 1675, 1540.

NMR (CDCl₃, δ, ppm): 3.40 (s, 3H), 3.54 (s, 2H), 3.71 (s, 3H), 4.20 (s,2H), 4.46 (d, 1H), 4.82 (s, 1H), 4.95 (s, 1H), 5.33 (s, 1H), 5.52 (s,1H), 6.42 (d, 1H), 7.23 (s, 5H).

EXAMPLES 43 TO 52

The procedure of Example 42 was repeated by using compounds (Ic) whereinR¹ and R² are as shown in Table 6 each in an amount of 50 mg andemploying the conditions indicated in Tables 6 and 7. As a result, therewere obtained compounds (Ib) represented by the formula ##STR82##wherein R¹, R² and R⁴ are as indicated in Table 8 and having theproperties listed in Tables 8 and 9.

                                      TABLE 6                                     __________________________________________________________________________    Compound (Ic)            Water - Organic solvent                              Example                                                                            R.sup.1                                                                             R.sup.2   R.sup.4                                                                           (ml)       (ml)                                      __________________________________________________________________________    43   PhCH.sub.2 --                                                                       CH.sub.3 --                                                                             CH.sub.3 --                                                                       5 - methyl acetate                                                                       5                                         44   PhCH.sub.2 --                                                                       PhCH.sub.2 --                                                                           CH.sub.3 --                                                                       3 - methylene chloride                                                                   5                                         45   PhCH.sub.2 --                                                                       PhCH.sub.2 --                                                                           CH.sub.3 --                                                                       3 - methylene chloride                                                                   5                                         46   PhCH.sub.2 --                                                                       CCl.sub.3 CH.sub.2 --                                                                   CH.sub.3 --                                                                       3 - 1,2-dichloroethane                                                                   5                                         47   PhCH.sub.2 --                                                                       CH.sub.3 --                                                                             C.sub.2 H.sub.5 --                                                                3 - chlorobenzene                                                                        5                                         48   PhOCH.sub.2 --                                                                      CH.sub.3 --                                                                             CH.sub.3 --                                                                       3 - methylene chloride                                                                   5                                         49   PhOCH.sub.2 --                                                                      PhCH.sub.2 --                                                                           CH.sub.3 --                                                                       3 - chloroform                                                                           5                                         50   PhOCH.sub.2 --                                                                      CCl.sub.3 CH.sub.2 --                                                                   CH.sub.3 --                                                                       3 - methylene chloride                                                                   5                                         51   PhOCH.sub.2 --                                                                      p-NO.sub.2 --PhCH.sub.2 --                                                              CH.sub.3 --                                                                       3 - methylene chloride                                                                   5                                         52   PhOCH.sub.2 --                                                                      p-CH.sub.3 O--PhCH.sub.2 --                                                             CH.sub.3 --                                                                       3 - methylene chloride                                                                   5                                         __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________         Hydrochloric                                                                           Mineral acid       Amount      Yield                                 acid or  or organic   Electrode                                                                           (F/mol)                                                                            Temperature                                                                          (%)                              Example                                                                            chloride (g)                                                                           acid (ml)    (1)   (2)  (°C.)                                                                         (3)                              __________________________________________________________________________    43   NaCl 1   Sulfuric acid                                                                          0.05                                                                              Pt    5    18-20  89                               44   NaCl 1   Acetic acid                                                                            0.08                                                                              C     5    10-15  83.5                             45   MgCl.sub.2                                                                         1   Acetic acid                                                                            0.08                                                                              Pt    5    16-18  81.8                             46   NaCl 1   Acetic acid                                                                            0.08                                                                              Pt    3    18-21  83.5                             47   KCl  1   Sulfuric acid                                                                          0.05                                                                              Pt    5     5-10  88.2                             48   NaCl 1   Sodium hydrogen-                                                                       0.05 g                                                                            Pt    5    20-23  82.5                                           sulfate                                                         49   35% HCl                                                                            0.2 ml                                                                            --           Pt    5    20-21  82.0                             50   NaCl 1   Sulfuric acid                                                                          0.05                                                                              Pt    5    18-21  88.0                             51   NaCl 1   Formic acid                                                                            0.08                                                                              Pt    5    10-12  81.5                             52   NaCl 1   Acetic acid                                                                            0.08                                                                              Pt    5    10-12  82.0                             __________________________________________________________________________     Note:                                                                         (1) Pt: Platinum electrode (1.5 × 2 cm.sup.2), C: Carbon electrode      (1.5 × 2 cm.sup.2)                                                      (2) Amount of electric charge (faraday) per mole of the compound (Ic)         (3) Yield of the compound (Ib) resulting from the purification by column      chromatography.                                                          

                                      TABLE 8                                     __________________________________________________________________________    Compound (Ib)                IR                                               Example                                                                             R.sup.1                                                                              R.sup.2    R.sup.4                                                                            (.sup.ν C=O, cm.sup.-1)                       __________________________________________________________________________    43    PhCH.sub.2 --                                                                        CH.sub.3 --                                                                              CH.sub.3 --                                                                        Same as in Ex. 42                                44    PhCH.sub.2 --                                                                        PhCH.sub.2 --                                                                            CH.sub.3 --                                                                        1782, 1762, 1665                                 45    PhCH.sub.2 --                                                                        PhCH.sub.2 --                                                                            CH.sub.3 --                                                                        Same as in Ex. 44                                46    PhCH.sub.2 --                                                                        CCl.sub.3 CH.sub.2 --                                                                    CH.sub.3 --                                                                        1785, 1758, 1675                                 47    PhCH.sub.2 --                                                                        CH.sub.3 --                                                                              C.sub.2 H.sub.5 --                                                                 1783, 1755, 1670                                 48    PhOCH.sub.2 --                                                                       CH.sub.3 --                                                                              CH.sub.3 --                                                                        1785, 1760, 1683                                 49    PhOCH.sub.2 --                                                                       PhCH.sub.2 --                                                                            CH.sub.3 --                                                                        1780, 1755, 1685                                 50    PhOCH.sub.2 --                                                                       CCl.sub.3 CH.sub.2 --                                                                    CH.sub.3 --                                                                        1780, 1760, 1690                                 51    PhOCH.sub.2 --                                                                       p-NO.sub.2 --PhCH.sub.2 --                                                               CH.sub.3 --                                                                        1785, 1755, 1685                                 52    PhOCH2 p-CH.sub.3 O--PhCH.sub. 2 --                                                             CH.sub.3 --                                                                        1785, 1760, 1690                                 __________________________________________________________________________

                  TABLE 9                                                         ______________________________________                                        Example     .sup.1 H--NMR (δ, ppm)                                      ______________________________________                                        43          Same as in Example 42                                             44          3.42 (s, 3H), 3.55 (s, 2H), 4.25 (s, 2H),                                     4.45 (d, 1H), 4.82 (s, 1H), 4.95 (s, 1H),                                     5.12 (s, 2H), 5.52 (s, 1H), 6.42 (d, 1H),                                     6.8-7.45 (10H)                                                    45          Same as in Example 44                                             46          3.43 (s, 3H), 3.54 (s, 2H), 4.30 (s, 2H),                                     4.47 (d, 1H), 4.75 (s, 2H), 4.82 (s, 1H),                                     4.95 (s, 1H), 5.50 (s, 1H), 6.50 (d, 1H),                                     7.30 (s, 5H)                                                      47          3.50 (s, 2H), 3.75 (s, 3H), 4.18 (s, 2H),                                     4.48 (d, 1H), 4.85 (s, 1H), 4.70 (s, 1H),                                     5.43 (s, 1H), 5.60 (s, 1H), 6.7-7.4 (6H)                          48          3.38 (s, 3H), 3.69 (s, 3H), 4.20 (s, 2H),                                     4.42 (d, 1H), 4.52 (s, 2H), 4.82 (s, 1H),                                     4.95 (s, 1H), 5.33 (s, 1H), 5.50 (s, 1H),                                     6.5-7.5 (6H)                                                      49          3.40 (s, 3H), 4.25 (s, 2H), 4.50 (d, 1H),                                     4.55 (s, 2H), 4.85 (s, 1H), 4.90 (s, 1H),                                     5.12 (s, 2H), 5.35 (s, 1H), 5.55 (s, 1H),                                     6.5-7.5 (11H)                                                     50          3.41 (s, 3H), 4.23 (s, 2H), 4.47 (d, 1H),                                     4.52 (s, 2H), 4.75 (s, 2H), 4.82 (s, 1H),                                     4.97 (s, 1H), 5.36 (s, 1H), 5.53 (s, 1H),                                     6.45-7.5 (6H)                                                     51          3.40 (s, 3H), 4.22 (s, 2H), 4.45 (d, 1H),                                     4.53 (s, 2H), 4.82 (s, 1H), 4.98 (s, 1H),                                     5.20 (s, 2H), 5.33 (s, 1H), 5.52 (s, 1H),                                     6.45 (d, 1H), 6.6-8.3 (9H)                                        52          3.41 (s, 3H), 3.87 (s, 3H), 4.20 (s, 2H),                                     4.42 (d, 1H), 4.52 (s, 2H), 4.82 (s, 1H),                                     4.95 (s, 1H), 5.18 (s, 2H), 5.33 (s, 1H),                                     5.52 (s, 1H), 6.5-7.5 (10H)                                       ______________________________________                                    

EXAMPLE 53

In 3 ml of methylene chloride was dissolved 50 mg of a compound (Ia)wherein R¹ phenoxymethyl, R² is 2,2,2-trichloroethyl, R³ is ##STR83##and R⁴ is methyl. To the solution were added 5 ml of a saturated aqueoussolution of sodium chloride and 0.07 ml of sulfuric acid. The mixturewas stirred to obtain a solution comprising two liquid phases.Electrolysis was continued for 20 minutes with stirring at a temperatureof 18° to 20° C. and a cathode current density of 10 mA/cm² by usingplatinum electrodes (1.5×2 cm²). After the completion of the reaction,the methylene chloride was separated from the reaction mixture. Then theaqueous phase was extracted with methylene chloride. The extract waswashed with a saturated aqueous solution of sodium chloride and driedover anhydrous sodium sulfate. The solvent was removed at reducedpressure. The residue was purified by silica gel column chromatographyusing a 5:1 benzene-acetic acid mixture as a developer, giving 48.4 mgof a compound (Ib) wherein R¹ is phenoxymethyl, R² is2,2,2-trichloroethyl, R³ is ##STR84## R⁴ is methyl and X is Cl. Yield90.8%.

IR (CHCl₃, .sup.ν max, cm⁻¹): 3370, 1780, 1750, 1695.

¹ H-NMR (CDCl₃, δ, ppm): 2.08 (s, 3H), 4.17 (s, 2H), 4.49 (s, 2H), 4.78(s, 1H), 4.80 (s, 2H), 5.05 (s, 2H), 5.42 (q, 1H), 5.96 (d, 1H), 6.6-7.4(m, 5H), 7.65 (d, 1H).

EXAMPLE 54

Into a reactor were placed 30.5 mg of a compound (Ia) wherein R¹ isphenoxymethyl, R² is methyl, R³ is

    --S--SO.sub.2 --R.sup.5

and R⁵ is phenyl, 1.0 g of NaCl, 3 ml of water, 5 ml of methylenechloride and 0.07 ml of conc. sulfuric acid. The mixture was stirred toobtain a solution comprising two liquid phases. Electrolysis wascontinued for 15 minutes by use of platinum electrodes while passing anelectric charge of 5 F/mol. After the completion of the reaction, thesubsequent procedure of Example 42 was repeated to prepare 22.9 mg of acompound (Ib) wherein R¹ is phenoxymethyl, R² is methyl, R³ is

    --S--SO.sub.2 --R.sup.5,

R⁵ is phenyl and X is Cl. Yield 92.4%.

IR (cm⁻¹): 3060, 2960, 1780, 1740, 1655, 1600, 1595, 1520, 1490, 1440,1322, 1235, 1135, 1070.

NMR (CDCl₃, δ, ppm): 3.72 (s, 3H), 4.10 (s, 2H), 4.40 (s, 2H), 4.82 (s,1H), 5.12 (s, 1H), 5.26 (s, 1H), 5.1-5.35 (m, 1H), 5.94 (d, J=6.6 Hz),6.7-8.0 (m, 11H).

EXAMPLE 55

Into a reactor were placed 39.7 mg of a compound (Ia) wherein R¹ isbenzyl, R² is methyl and R³ is ##STR85## 3 ml of methylene chloride and15 ml of a saturated aqueous solution of sodium chloride. Then themixture was stirred to obtain a solution comprising two liquid phases.Electrolysis was continued for 2 hours at a temperature of 19° C. and acathode current density of 13 mA/cm² by using platinum electrodes whilepassing an electric charge of 32 F/mol. After the completion of thereaction, the subsequent procedure of Example 42 was repeated, giving38.2 mg of a compound (Ib) as a colorless oily product wherein R¹ isbenzyl, R² is methyl, R³ is ##STR86## and X is Cl. Yield 89.5%.

NMR (CDCl₃, δ, ppm): 2.83 (s, 4H), 3.72 (s, 2H), 3.77 (s, 3H), 4.25 (s,2H), 5.05 (s, 1H), 5.14 (d, 1H), 5.27 (dd, 1H), 5.40 (s, 1H), 5.59 (s,1H), 7.0-7.5 (m, 6H).

EXAMPLE 56

Into a reactor were placed 34.65 mg of a compound (Ia) wherein R¹ isphenoxymethyl, R² is methyl, R³ is ##STR87## and, R⁶ and R⁷ are bothethyl, 4.5 g of magnesium chloride (6H₂ O), 3 ml of water, 3 ml of ethylacetate and 0.07 ml of conc. sulfuric acid. The mixture was stirred toobtain a solution comprising two liquid phases. Electrolysis wascontinued for 30 minutes with stirring at a temperature of 18° to 20° C.and a cathode current density of 30 mA/cm² by using platinum electrodeswhile passing an electric charge of 8 F/mol. After the completion of thereaction, the subsequent procedure of Example 42 was effected, giving34.34 mg of a compound (Ib) wherein R¹ is phenoxymethyl, R² is methyl,R³ is ##STR88## R⁶ and R⁷ are both ethyl and X is Cl. Yield 92.8%.

IR (cm⁻¹): 2980, 2960, 2940, 1780, 1745, 1690, 1603, 1580, 1495, 1440,1250, 1010, 810, 740, 720.

NMR (CDCl₃, δ, ppm): 1.31 (dt, 6H), 3.78 (s, 3H), 4.09 (m, 4H), 4.20 (s,2H), 4.50 (s, 2H), 5.10 (s, 1H), 5.21 (s, 1H), 5.55 (s, 1H), 5.2-5.85(m, 2H), 6.7-7.4 (m, 5H), 7.6 (d, J=10.5 Hz, 1H).

EXAMPLE 57

The procedure of Example 42 was repeated by using a compound (Ia)wherein R¹ is p-chlorobenzyl, R² is p-nitrobenzyl, R³ is ##STR89## andR⁴ is isopropyl. Thereby there was obtained a compound (Ib) wherein R¹is p-chlorobenzyl, R² is p-nitrobenzyl, R³ is ##STR90## R⁴ is isopropyland X is Cl in a yield of 84%. The compound was identified by IR andNMR.

    ______________________________________                                        Elementary analysis                                                                    C           H      N                                                 ______________________________________                                        Calcd. (%):                                                                              50.98         4.45   6.86                                          Found (%): 50.61         4.44   6.85                                          ______________________________________                                    

EXAMPLE 58

The procedure of Example 42 was repeated by using a compound (Ia)wherein R¹ is p-nitrophenoxymethyl, R² is phenoxymethyl, R³ is ##STR91##and R⁴ is tert-butyl. As a result, there was obtained a compound (Ib)wherein R¹ is p-nitrophenoxymethyl, R² is phenoxymethyl, R³ is ##STR92##R⁴ is n-butyl and X is Cl. Yield 82.0%. The compound was identified byIR and NMR.

    ______________________________________                                        Elementary analysis                                                                    C           H      N                                                 ______________________________________                                        Calcd. (%):                                                                              51.96         4.85   6.73                                          Found (%): 51.92         4.84   6.75                                          ______________________________________                                    

EXAMPLE 59

The procedure of Example 53 was repeated by using a compound (Ia)wherein R¹ is p-methoxybenzyl, R² is 2-chloroethyl, R³ is ##STR93## andR⁴ is ethyl. As a result, there was produced a compound (Ib) wherein R¹is p-methoxybenzyl, R² is 2-chloroethyl, R³ is ##STR94## R⁴ is ethyl andX is Cl. Yield 87.0%. The compound was identified by IR and NMR.

    ______________________________________                                        Elementary analysis                                                                    C           H      N                                                 ______________________________________                                        Calcd. (%):                                                                              51.06         5.07   5.41                                          Found (%): 51.08         5.06   5.37                                          ______________________________________                                    

EXAMPLE 60

The procedure of Example 53 was repeated by using a compound (Ia)wherein R¹ is p-methoxyphenoxymethyl, R² is diphenylmethyl, R³ is##STR95## and R⁴ is n-propyl. As a result, there was obtained a compound(Ib) wherein R¹ is p-methoxyphenoxymethyl, R² is diphenylmethyl, R³ is##STR96## R⁴ is n-propyl and X is Cl. Yield 85.5%. The compound wasidentified by IR and NMR.

    ______________________________________                                        Elementary analysis                                                                    C           H      N                                                 ______________________________________                                        Calcd. (%):                                                                              62.70         5.43   4.30                                          Found (%): 62.73         5.40   4.29                                          ______________________________________                                    

EXAMPLE 61

The procedure of Example 54 was repeated by using a compound (Ia)wherein R¹ is benzyl, R² is p-nitrophenoxymethyl, R³ is

    --S--SO.sub.2 --R.sup.5

and R⁵ is phenyl, giving a compound (Ib) wherein R¹ is benzyl, R² isp-nitrophenoxymethyl, R³ is

    --S--SO.sup.2 --R.sup.5,

R⁵ is phenyl and X is Cl. Yeild 83%. The compound was identified by IRand NMR.

    ______________________________________                                        Elementary analysis                                                                    C           H      N                                                 ______________________________________                                        Calcd. (%):                                                                              52.76         3.98   6.37                                          Found (%): 52.79         3.97   6.38                                          ______________________________________                                    

EXAMPLE 62

A compound (Ib) wherein R¹ is phenoxymethyl, R² is p-methoxybenzyl, R³is

    --S--SO.sub.2 --R.sup.5,

R⁵ is p-chlorophenyl and X is Cl was prepared by the same process as inExample 54 with the exception of using a compound (Ia) wherein R¹, R²,R³ and R⁵ are as defined above. Yield 86.5%. The compound (Ib) wasidentified by IR and NMR.

    ______________________________________                                        Elementary analysis                                                                    C           H      N                                                 ______________________________________                                        Calcd. (%):                                                                              53.01         4.16   4.12                                          Found (%): 53.04         4.15   4.15                                          ______________________________________                                    

EXAMPLE 63

A compound (Ib) wherein R¹ is p-nitrobenzyl, R² is phenoxymethyl, R³ is##STR97## R⁶ and R⁷ are both n-propyl and X is Cl was prepared in thesame manner as in Example 56 with the exception of using a compound (Ia)wherein R¹, R², R³, R⁶ and R⁷ are defined above. Yield 83%.

    ______________________________________                                        Elementary analysis                                                                    C           H      N                                                 ______________________________________                                        Calcd. (%):                                                                              50.91         5.17   6.14                                          Found (%): 50.94         5.14   6.15                                          ______________________________________                                    

EXAMPLE 64

A compound (Ib) wherein R¹ is phenoxymethyl, R² is benzyl, R³ is##STR98## and X is Cl was prepared in the same manner as in Example 55with the exception of using a compound (Ia) wherein R¹, R² and R³ are asdefined above. Yield 83.5%. The compound was identified by IR and NMR.

    ______________________________________                                        Elementary analysis                                                                    C           H      N                                                 ______________________________________                                        Calcd. (%):                                                                              60.04         4.23   6.78                                          Found (%): 60.01         4.22   6.81                                          ______________________________________                                    

EXAMPLE 65

Synthesis of the ester of3-chloromethyl-7-phenylacetamide-3-cephem-4-carboxylic acid and benzylalcohol having the formula ##STR99##

Into a reactor were placed 101 mg of the ester of3-chloromethyl-2-(3-phenylacetamide-4-phenylsulfonylthio-2-azetidinone-1-yl)-3-butenoicacid and benzyl alcohol having the formula ##STR100## and 1 ml of drieddimethylformamide (DMF). The contents of the reactor were mixed togetherto obtain a uniform solvent. The reactor was cooled to -25° C. by beingplaced into a Dry Ice-acetone bath. 28% ammonia water (15.5 μl) wasadded and the mixture was stirred for 1 hour while maintaining thetemperature at -30° to -20° C. After the completion of the reaction,thereto were added 5 drops of 5% hydrochloric acid and then about 30 mlof ethyl acetate. The reaction mixture was poured into an aqueoussolution of sodium chloride with ice floating thereon, therebyseparating the organic phase. The organic phase thus obtained was washedtwice with a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography, giving 68 mg of the ester of3-chloromethyl-7-phenylacetamide-3-cephem-4-carboxylic acid and benzylalcohol. Yield 88%. The compound was identified by IR and NMR.

IR (CHCl₃, cm⁻¹): 1790, 1730, 1682.

NMR (CDCl₃, δ, ppm): 3.32 and 3.60 (2H, ABq, 18 Hz), 3.53 (2H, s), 4.31and 4.45 (2H, ABq, 12 Hz), 4.86 (1H, d, 5 Hz), 5.20 (2H, s), 5.77 (1H,d.d, 5 Hz, 9.2 Hz), 6.43 (1H, d, 9.2 Hz), 7.27 (5H, s), 7.33 (5H, s).

EXAMPLE 66 Preparation of the ester of3-chloromethyl-7-phenylacetamide-3-cephem-4-carboxylic acid and benzylalcohol.

Into a reactor were placed 34 mg of the ester of3-chloromethyl-2-(3-phenylacetamide-4-phenylsulfonylthio-2-azetidinone-1-yl)-3-butenoicacid and benzyl alcohol and 0.4 ml of dried DMF, followed by mixing ofthe contents to obtain a uniform solvent. The reactor was cooled to -35°C. by being placed into a Dry Ice-acetone bath. Subsequently into thereactor was charged 0.125 ml of the DMF prepared by forcing ammonia gasthereinto to a ammonia concentration of 11.4 mg/ml. The resultingmixture was stirred for 1 hour while being maintained at -40° to -35° C.After the completion of the reaction, the reaction mixture was subjectedto the same treatment as in Example 65. As a result, there was obtained18.8 mg of the ester of3-chloromethyl-7-phenylacetamide-3-cephem-4-carboxylic acid and benzylalcohol. Yield 74%.

The compound thus obtained was analyzed with the results identical withthose obtained in Example 65.

EXAMPLES 67 TO 76

The procedure of Example 65 was repeated by using the azetidinonederivatives (Ib) having the formula ##STR101## wherein R¹, R² and R⁴ areas shown in Table 10 and employing the reaction conditions as indicatedin Table 10. As a result, there were obtained derivatives of3-chloromethyl-3-cephem(IV) having the formula ##STR102## and shown inTable 11 as having the properties set forth therein.

                                      TABLE 10                                    __________________________________________________________________________    Derivative (Ib)                     Ammonia                                                              Amount                                                                             DMF water                                                                              Temp. Time                                                                             Yield                       Example                                                                            R.sup.1                                                                             R.sup.2  R.sup.4                                                                              (mg) (ml)                                                                              (μl)                                                                            (°C.)                                                                        (hr)                                                                             (%)                         __________________________________________________________________________    67   PhCH.sub.2 --                                                                       CH.sub.3 --                                                                            Ph     100  0.5 36   -30/-20                                                                             1  72                          68   PhCH.sub.2 --                                                                       CH.sub.3 --                                                                            p-CH.sub.3 --Ph-                                                                     48   0.5 16.5 -30/-20                                                                             1  59                          69   PhCH.sub.2 --                                                                       CH.sub.3 --                                                                            p-Cl--Ph-                                                                            53   0.5 17.5 -30/-20                                                                             1  70                          70   PhCH.sub.2 --                                                                       CH.sub.3 --                                                                            p-NO.sub.2 --Ph-                                                                     45   0.5 7.5  -30/-20                                                                             1  84                          71   PhCH.sub.2 --                                                                       CH.sub.3 --                                                                            o-NO.sub.2 --Ph-                                                                     48   0.5 15.5 -30/-20                                                                             1  44                          72   PhCH.sub.2 --                                                                       PhCH.sub.2 --                                                                          p-CH.sub.3 O--Ph-                                                                    45   0.5 13   -30/-20                                                                             1  72                          73   PhCH.sub.2 --                                                                       PhCH.sub.2 --                                                                          p-NO.sub.2 --Ph-                                                                     43   0.5 6.1  -40/-35                                                                             1  70                          74   PhCH.sub.2 --                                                                       --CH.sub.2 CCl.sub.3                                                                   p-NO.sub.2 --Ph-                                                                     47   0.5 12.6 -30/-20                                                                             1  51                          75   PhCH.sub.2                                                                          p-NO.sub.2 --PhCH.sub.2 --                                                             p-NO.sub.2 --Ph-                                                                     56   0.5 15   -30/-20                                                                             1  67                          76   PhOCH.sub.2 --                                                                      PhCH.sub.2                                                                             p-NO.sub.2 --Ph                                                                      60   0.5 16.5 -30/-20                                                                             1  83                          __________________________________________________________________________

                                      TABLE 11                                    __________________________________________________________________________                      IR                                                          Example                                                                            R.sup.1                                                                             R.sup.2                                                                              (CHCl.sub.3, cm.sup.-1)                                                               NMR (CDCl.sub.3)                                    __________________________________________________________________________    67, 68,                                                                            PhCH.sub.2 --                                                                       CH.sub.3                                                                             1787    3.38 and 3.60 (2H, ABq, 18Hz),                      69, 70,           1730    3.60 (2H, s), 3.83 (3H, s),                         71                1680    4.40 and 4.57 (2H, ABq, 12Hz),                                                4.95 (1H, d, 5Hz),                                                            5.78 (1H, d.d, 5Hz, 9.2Hz),                                                   6.18 (1H, d, 9.2Hz), 7.27 (5H, s)                   72, 73                                                                             PhCH.sub.2 --                                                                       PhCH.sub.2 --                                                                        Identical with the values obtained                                            in Example 65                                               74   PhCH.sub.2 --                                                                       CH.sub.2 CCl.sub.3                                                                   1797    3.50 and 3.67 (2H, ABq, 18Hz)                                         1725    3.65 (2H, s), 4.51 (2H, s),                                           1680    4.80 and 4.97 (2H, ABq, 12Hz),                                                5.03 (1H, d, 5Hz),                                                            5.88 (1H, d.d, 5Hz, 9.2Hz),                                                   6.28 (1H, d, 9.2Hz), 7.30 (5H, s)                   75   PhCH.sub.2 --                                                                       p-NO.sub.2 --Ph-                                                                     1790    3.45 and 3.63 (2H, ABq, 18Hz),                                        1730    3.63 (2H, s),                                                         1695    4.41 and 4.57 (2H, ABq, 12Hz),                                                4.97 (1H, d, 5Hz), 5.37 (2H, s),                                              5.87 (1H, d.d, 5Hz, 9.2Hz),                                                   6.3 (1H, d, 9.2Hz), 7.30 (5H, s),                                             7.55 (2H, d, 9Hz), 8.21 (2H, d, 9Hz)                76   PhOCH.sub.2 --                                                                      PhCH.sub.2 --                                                                        1790    3.50 and 3.55 (2H, ABq, 18Hz),                                        1730    4.40 and 4.53 (2H, ABq, 12Hz),                                        1690    4.52 (2H, s), 4.97 (1H, d, 5Hz),                                              5.29 (2H, s),                                                                 5.73 (1H, d.d, 5Hz, 9.2Hz),                                                   6.48 (1H, d, 9.2Hz), 7.32 (5H, s),                                            6.7-7.6 (5H, m)                                     __________________________________________________________________________

We claim:
 1. A process for preparing an azetidinone derivativerepresented by the formula: ##STR103## wherein R¹ is lower alkylmono-substituted with aryl or with aryloxy, the aryl being optionallysubstituted with hydroxy, methoxy, chloro or nitro and the aryloxy beingoptionally substituted with hydroxy, methoxy or nitro;R² is lower alkylmono- or di-substituted with aryl or with aryloxy, the aryl beingoptionally substituted with methoxy, chloro or nitro, and the aryloxybeing optionally substituted with nitro, or R² is lower alkyl optionallymono- or tri-substituted with halogen; R⁵ is aryl optionally substitutedwith hydroxy, chloro, nitro, methyl or methoxy; and X' is a halogen, theprocess comprising subjecting to electrolysis an azetidinone derivativerepresented by the formula: ##STR104## wherein R¹, R² and R⁵ are asdefined above in the presence of at least one member selected from thegroup consisting of hydrohalogenic acid and halide.
 2. A processaccording to claim 1 wherein the electrolysis is conducted byincorporating mineral acid or organic acid in the reaction system.
 3. Aprocess according to claim 1 wherein the electrolysis is conducted in anester of lower carboxylic acid or hydrocarbon halide.
 4. A processaccording to claim 1 wherein the electrolysis is conducted at atemperature of -30° to 60° C.